The overall goal of this research project is to determine whether changes in high-energy phosphate metabolism are important characteristics of the hypertrophying heart. Our approach is two-folds: to characterize the properties of the creatine kinase (CK) isozymes, those proteins regulating the average cellular concentrations of ATP and creatine phosphate (CrP), using traditional biochemical techniques and to define the dynamics of transfer of the high energy phosphate group between creatine (Cr) and ADP using P-31 NMR spectroscopy and saturation transfer techniques. Both in canine models of cardiac hypertrophy stimulated by volume overload and secondary to hypertension (unilateral nephrectomy) and in the hearts of the spontaneously hypertensive rat, we have found changes in the distribution and concentrations of the creatine kinase isozymes. Specifically, hypertrophying hearts contain more of the fetal type isozymes (BB- and MB-CK) than normal hearts. In hearts demonstrating ventricular dysfunction the tissue contents of the two isozymes characteristic of well-differentiated adult cardiac muscle, namely the MM and mitochondrial CK isozymes, are significantly depressed. In order to define the consequences of these changes in isozyme distribution on energy metabolism, we have used P-31 NMR spectroscopy to measure unidirectional rate constants of ATP and CrP synthesis via the CK reaction were measured in Neely-Morgan perfused working hearts isolated from normal and spontaneously hypertensive rats. Preliminary results suggest that the rate of transfer of phosphate between ADP and creatine is reduced 3 to 10 fold in hearts with demonstrated ventricular dysfunction secondary to cardiac hypertrophy, but not in compensated hearts from age matched control animals. We propose to extend these studies in order to test whether a derangement in energy metabolism occurs at either of th two transition points important for understanding the ontogeny of cardiac hypertrophy: the onset of hypertrophy and the transition to failure. This approach provides the unique opportunity to obtain biochemical fluxes and mechanical performance simultaneously in beating hearts and should provide new information important to our understanding of cardiac hypertrophy.